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Agonists and antagonists bind to an A-A interface in the heteromeric 5-HT(3)AB receptor
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Lochner, M. and Lummis, S. C. R. (2010) Agonists and antagonists bind to an A-A interface in the heteromeric 5-HT(3)AB receptor. Biophysical Journal, Vol.98 (No.8). pp. 1494-1502. doi:10.1016/j.bpj.2009.12.4313 ISSN 0006-3495.
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Official URL: http://dx.doi.org/10.1016/j.bpj.2009.12.4313
Abstract
The 5-HT3 receptor is a member of the Cys-loop family of transmitter receptors. It can function as a homopentamer (5-HT3A-only subunits) or as a heteropentamer. The 5-HT(3)AB receptor is the best characterized heteropentamer. This receptor differs from a homopentamer in its kinetics, voltage dependence, and single-channel conductance, but its pharmacology is similar. To understand the contribution of the 5-HT3B subunit to the binding site, we created homology models of 5-HT(3)AB receptors and docked 5-HT and granisetron into AB, BA, and BB interfaces. To test whether ligands bind in any or all of these interfaces, we mutated amino acids that are important for agonist and antagonist binding in the 5-HT3A subunit to their corresponding residues in the 5-HT3B subunit and vice versa. Changes in [H-3]granisetron binding affinity (K-d) and 5-HT EC50 were determined using receptors expressed in HEK-293 cells and Xenopus oocytes, respectively. For all A-to-B mutant receptors, except T181N, antagonist binding was altered or eliminated. Functional studies revealed that either the receptors were nonfunctional or the EC50 values were increased. In B-to-A mutant receptors there were no changes in K-d, although EC50 values and Hill slopes, except for N170T mutant receptors, were similar to those for 5-HT(3)A receptors. Thus, the experimental data do not support a contribution of the 5-HT3B subunit to the binding pocket, and we conclude that both 5-HT and granisetron bind to an AA binding site in the heteromeric 5-HT(3)AB receptor.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Subjects: | Q Science > QH Natural history > QH301 Biology | ||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||
| Journal or Publication Title: | Biophysical Journal | ||||
| Publisher: | Biophysical Society | ||||
| ISSN: | 0006-3495 | ||||
| Official Date: | 21 April 2010 | ||||
| Dates: |
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| Volume: | Vol.98 | ||||
| Number: | No.8 | ||||
| Number of Pages: | 9 | ||||
| Page Range: | pp. 1494-1502 | ||||
| DOI: | 10.1016/j.bpj.2009.12.4313 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access | ||||
| Funder: | Wellcome Trust, Swiss National Science Foundation | ||||
| Grant number: | PA00A-105073 |
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